Although the physiological mechanism is not completely understood, it has been reported that animals placed on a purified, chromium-free diet for several weeks displayed greatly impaired glucose tolerance, i.e. the ability to maintain blood glucose at normal levels. It was found that a diet containing chromium-rich Brewer's yeast would eliminate this impairment and that blood glucose levels would return to normal. The presence of chromium as an organic salt in foods was also found to increase glucose oxidation in humans, particularly when extracts of Brewer's yeast containing chromium where added. In addition, oral administration of such material to a diabetic individual was found to influence the pancreas to produce normal amounts of insulin.
The relationship between chromium content in food and its effects on glucose oxidation are discussed, for example in Toepfer, et al., “Chromium Foods in Relation to Biological Activity,” J. Agr. Food. Chem. 21:69 (1973).
Trivalent chromium (Cr+3) has long been known to be essential for proper insulin function and, thus, plays a vital role in protein, fat and carbohydrate metabolism. In the U.S., studies show that the diets of nine out of 10 Americans are deficient in chromium, while chromium levels are known to decline with age. Stress, exercise and pregnancy are known to increase chromium losses from the body. Chromium deficiency can lead to symptoms associated with adult-onset diabetes, obesity and cardiovascular disease. In studies, supplemental trivalent chromium has improved blood sugar levels or other symptoms in people with glucose intolerance, type 1 diabetes, type 2 diabetes, steroid-induced diabetes and gestational diabetes. Chromium is also known to increase lean body mass, improve blood lipid profiles and lower blood pressure levels. However, chromium bioavailability and biological activity are dependent upon the ligand to which chromium is bound. (Mertz, W. Chromium Occurrence and Function in Biological Systems, Physiological Reviews, 49(2): 163-239, 207, 1969 (and see generally for a discussion of chromium's biological function).
Inorganic chromium chloride, for example, is poorly absorbed by the body, typically less than one percent, and has poor bioavailability. Elucidating the structure, function and mode of action of the biologically active form of chromium, however, has proved enigmatic. (Mertz W. Chromium in human nutrition: a review. J. Nutr. 1993; 123:626-633; Lukaski H. C. Chromium as a supplement. Annu. Rev. Nutr. 1999; 19:279-301.)
Various proposals have been developed as to the composition of a biologically active chromium composition called glucose tolerance factor (GTF). Walter Mertz has suggested that Brewer's yeast contained a biologically active form of trivalent chromium comprised of Cr3+, glycine, glutamate, cysteine, and nicotinic acid, which strongly potentiated the action of insulin and possess an ultraviolet absorbance maximum at about 260 nm. (Schwartz K, Mertz W: A glucose tolerance factor and its differentiation from factor 3. Arch Biochem Biophys 72: 515-518, 1957; Toepfer E W, Mertz W, Polansky M M, Roginski E E, Wolfe W R: Preparation of chromium containing material of glucose tolerance factor activity from Brewer's yeast extracts and by synthesis. J. Agricul Food Chem 25: 162-166, 1977.) However, extracting the biologically active fractions of chromium in Brewer's yeast involves complex processes, which are expensive on a commercial scale for use in chromium supplementation of chromium deficient diets or for individuals otherwise requiring chromium supplementation. Therefore, researchers have tried to overcome this problem by synthetically preparing biologically active chromium compounds. In this regard, see Cooper et al., Inorganica Chimica Acta 92:23-31 (1984), which is directed to the synthesis and analysis of possible components of GTF. In Cooper, various complexes of glycine, glutamic acid, glutamine, cysteine and nicotinic acid were formed and analyzed for glucose tolerance factor activity using a yeast assay. A number of complexes including Cr-(cysteine)2−, Cr-nicotinic acid-cysteine complexes of undetermined structure, and Cr-nicotinic acid glycine were tested but only Cr(glutamine)2(H2O)2+, Cr-nicotinic acid-glycine and the mixture of complexes of Cr(glycine)n(H2O)6-n+3 showed significant activity. In contrast, Cr(cysteine)2− and Cr-nicotinic-cysteine complexes were not active in the yeast bioassay.
Other chromium complexes have been proposed as well. Maciejewska et al., Transition Metal Chem. 27:473-480 (2002) tested the toxicity and determined structure data of seven mono- and poly-nuclear CrIII complexes with natural ligands: glycine, glutaminic, nicotinic and asparginic acid, cysteine, and glutathione. Gonzales-Vergara et al., Israel J. Chem. 21:18-22 (1981) synthesized CrCl3, CrEDTA, Cr(glycine)2(nicotinic acid)2, Cr(III)-pyridoxylideneglycylglycine-diaquo (Cr(III)-PGG-diaquo), and Cr(III)-PGG-(nicotinic acid)2, which were tested for retention in mice.
The importance of the B vitamin, niacin, to chromium's biological activity was elucidated by Walter Mertz, when it was discovered that chromium bound to niacin strongly potentiated the action of insulin in vitro, while chromium alone, niacin alone or chromium bound to isomers of niacin, including picolinic acid, had virtually no effect on insulin in vitro. (Mertz W, Effects and Metabolism of Glucose Tolerance Factor, Present Knowledge in Nutrition, 4th Edition, The Nutrition Foundation, Washington, D.C., Chapter 36, pp 365-372, 1976.)
Niacin can be bound to chromium in various configurations. A particular oxygen-coordinated niacin-bound chromium complex was developed and introduced commercially as ChromeMate® (Interhealth Nutraceuticals, Inc., Benecia, Calif.). (Jensen, U.S. Pat. No. 5,194,615). Subsequently, Cooper et al. determined that oxygen-coordinated niacin-bound chromium was up to 18-times more potent than other forms of niacin-bound chromium tested in vitro. (Cooper J, et al, Structure and Biological Activity of Nitrogen and Oxygen Coordinated Nicotinic Acid Complexes of Chromium, Inorganica Chimica Acta, 91:1-9, 1984.)
Further studies established the superior safety and efficacy of ChromeMate® over inorganic chromium chloride and chromium picolinate, two commercially available forms of trivalent chromium for dietary supplementation. (Jain S K, Rains J and Rogier K, Effect of Niacin-Bound Chromium Complex (NBC) on IL-6 Secretion and Oxidative Stress Caused by High Glucose (HC) in Cultured U397 Monocytes, FASEB, 20(4):132, Abs. 376.4, April 2006; Grant K E, Chandler R M, Castle A L, Ivy J L, Chromium and Exercise Training: Effect on Obese Women, Medicine & Science in Sports & Exercise, 29:992-998, 1997; Preuss H G, Gropec P L, Lieberman S and Anderson R A, Effects of Different Chromium Compounds on Blood Pressure and Lipid Peroxidation in Spontaneously Hypertensive Rats, Clinical Nephrology, 47:325-330, 1997; Stearns D M, Wise, Sr., J P, Patierno S R and Wetterhahn K E, Chromium (III) Picolinate Produces Chromosome Damage in Chinese Hamster Ovary Cells. The FASEB Journal, 9: 643-1648, 1995.) In human bioavailability equivalency studies, researchers at U. C. Davis demonstrated that ChromeMate® was 311% more bioavailable than chromium picolinate and 672% more than chromium chloride in animal models. (Olin et al., Comparative retention/absorption of 51chromium (51Cr) from 51Cr chloride, 51Cr nicotinate and 51Cr picolinate in a rat model, Trace Elements and Electrolytes, 11(4):182-186, 1994.)
John Vincent has proposed a naturally occurring oligopeptide, low-molecular-weight chromium-binding substance (LMWCr) or chromodulin. Chromodulin has been proposed to activate insulin receptor kinase activity. The oligopeptide possesses a molecular weight of 1500 Da and is comprised of four types of amino acid residues: glycine, cysteine, glutamate and aspartate. (Vincent J. B: The quest for the molecular mechanism of chromium action and its relationship to diabetes. Nutr. Rev. 58, 2000.)
Taken together, the ligands of four amino acids, glycine, cysteine, glutamate and aspartate, and niacin are important for bioactive chromium complexes. (Yamamoto A., Wada O, Ono T: Isolation of a biologically active low-molecular-mass chromium compound from rabbit liver. Eur. J. Biochem. 165: 627-631, 1987; Davis C M, Vincent J B, Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36: 4382-4385, 1997.)
Another proposal supports the use of the amino acid histidine for GTF activity, U.S. Pat. No. 6,689,383, which is incorporated by reference in its entirety. Chromium histidine is said to be absorbed at least 50 percent better than chromium picolinate. In tests, men and women absorbed an average 3.1 μg of chromium from the chromium-histidine complex, compared with 1.8 μg from chromium picolinate, 0.4 μg from chromium chloride and 0.2 μg from chromium polynicotinate.
Alternatively, Yang et al. have shown the use of triphenylalanine as a ligand for a bioactive form of chromium. (Yang X, Palanichamy K, Ontko A C, Rao M N A, Fang C, Ren J, Sreejayan N: A newly synthetic chromium complex—chromium triphenylalanine improves insulin responsiveness and reduces whole body glucose tolerance, FEBS Letters 579 1458-1464, 2005.)
Synthesis of chromium amino acid nicotinate complex with mixture of glycine, glutamic acid and cysteine has been disclosed in U.S. Pat. No. 5,536,838, which is incorporated by reference in its entirety.
Chromium (III) 1:3 complexes of alpha amino acids are disclosed as animal nutritional supplements in Abdel-Monem et al., U.S. Pat. No. 7,247,328. Exemplified amino acids are methionine and leucine.
Gillota, U.S. Patent Publication No. 2003/0143311, discloses a recovery drink formula that includes chromium in the form of chromium dinicotinate glycinate.
In addition to a desire for safety, efficacy and bioavailability, there remains a desire for stability, solubility and the effect on taste and odor for use in food and beverage applications. Thus, while there have been many proposed chromium complexes for use in dietary supplements and food and beverage applications, most are inadequate or poorly characterized, and there still remains a need in the art for an improved synthetic chromium compound, which demonstrates improved biological activity, bioavailability, stability, solubility and/or sensory characteristics.